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Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial

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作者：
Lu Shun[1,*1] ; Wu Lin[2] ; Jian Hong[3] ; Cheng Ying[4] ; Wang Qiming[5] ; Fang Jian[6] ; Wang Ziping[6] ; Hu Yanping[7] ; Han Liang[8] ; Sun Meili[9] ; Miao Liyun[10] ; Ding Cuimin[11] ; Cui Jiuwei[12] ; Wang Ke[13] ; Li Baolan[14] ; Li Xingya[15] ; Ye Feng[16] ; Liu Anwen[17] ; Pan Yueyin[18] ; Cang Shundong[19] ; Zhou Hui[20] ; Sun Xing[21] ; Shen Yuping[20] ; Wang Shuyan[20] ; Zhang Wen[21] ; He Yue[20] ;
机构： [1]Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: shunlu@sjtu.edu.cn. [2]Department of Thoracic Medical Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. [3]Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. [4]Department of Oncology, Jilin Cancer Hospital, Changchun, China. [5]Department of Respiratory Medicine, Henan Cancer Hospital, Zhengzhou, China. [6]Department of Thoracic Medical Oncology, Peking University Cancer Hospital, Beijing Cancer Hospital, Beijing, China. [7]Department of Thoracic Medical Oncology, Hubei Cancer Hospital, Wuhan, China. [8]Department of Oncology, Xuzhou Central Hospital, Xuzhou, China. [9]Department of Oncology, Jinan Central Hospital affiliated to Shandong University, Jinan, China. [10]Department of Respiratory Medicine, Nanjing University Medical School affiliated Nanjing Drum Tower Hospital, Nanjing, China. [11]Department of Respiratory Medicine, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, China. [12]Department of Oncology, First Hospital of Jilin University, Changchun, China. [13]Department of Respiratory Medicine, Sichuan University West China Hospital, Chengdu, China. [14]Department of Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China. [15]Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [16]Department of Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, China. [17]Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China. [18]Department of Oncology, Anhui Provincial Hospital, Heifei, China. [19]Department of Oncology, Henan Provincial People's Hospital, Zhengzhou, China. [20]Department of Medical Science and Oncology, Innovent Biologics, Suzhou, China. [21]Department of Biostatistics and Information, Innovent Biologics, Suzhou, China.
出处：
DOI： 10.1016/S2213-2600(23)00135-2
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摘要：
In the first interim analysis of the ORIENT-31 trial, compared with chemotherapy alone, sintilimab plus bevacizumab biosimilar IBI305 plus chemotherapy (pemetrexed and cisplatin) significantly improved progression-free survival in patients with EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine-kinase inhibitor treatment. However, the benefit of anti-PD-1 or PD-L1 antibody added to chemotherapy in this patient population remains unclear, with no prospective evidence from phase 3 trials globally. We report the results from the prespecified second interim analysis of progression-free survival between sintilimab plus chemotherapy and chemotherapy alone, the updated results of sintilimab plus IBI305 plus chemotherapy, and preliminary overall survival results.This double-blind, randomised, placebo-controlled, phase 3 trial was done at 52 centres across China and included patients aged 18-75 years with locally advanced or metastatic (stage IIIB, IIIC, or IV according to the American Joint Committee on Cancer, eighth edition) EGFR-mutated non-squamous NSCLC, disease progression after EGFR tyrosine-kinase inhibitor treatment (according to the Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1]), and at least one measurable lesion (according to RECIST 1.1). Patients were randomly assigned (1:1:1), using an interactive web response system, to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus chemotherapy, or chemotherapy alone on day 1 of each 3-week cycle for four cycles, followed by maintenance therapy of sintilimab, IBI305, and pemetrexed. All study drugs were administered intravenously. The primary endpoint was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee. Data cutoff was March 31, 2022, unless otherwise specified. The study is registered at ClinicalTrials.gov, NCT03802240 (ongoing).Between July 11, 2019, and March 31, 2022, 1011 patients were screened and 476 were randomly assigned (158 to the sintilimab plus IBI305 plus chemotherapy group, 158 to the sintilimab plus chemotherapy group, and 160 to the chemotherapy alone group). The median follow-up duration for progression-free survival was 12·9 months (IQR 8·2-17·8) in the sintilimab plus IBI305 plus chemotherapy group, 15·1 months (8·0-19·5) in the sintilimab plus chemotherapy group, and 14·4 months (9·8-23·8) in the chemotherapy alone group. Sintilimab plus chemotherapy significantly improved progression-free survival compared with chemotherapy alone (median 5·5 months [95% CI 4·5-6·1] vs 4·3 months [4·1-5·3]; hazard ratio [HR] 0·72 [95% CI 0·55-0·94]; two-sided p=0·016). Significant progression-free survival benefit was sustained with sintilimab plus IBI305 plus chemotherapy compared with chemotherapy alone (median 7·2 months [95% CI 6·6-9·3]; HR: 0·51 [0·39-0·67]; two-sided p<0·0001). As of data cutoff (July 4, 2022), the median overall survival was 21·1 months (95% CI 17·5-23·9) for sintilimab plus IBI305 plus chemotherapy (HR 0·98 [0·72-1·34]) and 20·5 months (15·8-25·3) for sintilimab plus chemotherapy group (HR 0·97 [0·71-1·32]) versus 19·2 months (15·8-22·4) for chemotherapy alone; after adjusting for crossover, the HR for sintilimab plus IBI305 plus chemotherapy to chemotherapy alone ranged from 0·79 (0·57-1·09) to 0·84 (0·61-1·15) and the HR for sintilimab plus chemotherapy to chemotherapy alone ranged from 0·78 (0·57-1·08) to 0·84 (0·61-1·16). The safety results were generally consistent with those in the first interim analysis; in particular, treatment-related adverse events of grade 3 or worse occurred in 88 (56%) of 158 patients in the sintilimab plus IBI305 plus chemotherapy group, 64 (41%) of 156 patients in the sintilimab plus chemotherapy group, and 79 (49%) of 160 patients in the chemotherapy alone group.This is the first prospective phase 3 trial to show the benefit of anti-PD-1 antibody plus chemotherapy in patients with EGFR-mutated NSCLC who progressed on treatment with tyrosine-kinase inhibitors. Compared with chemotherapy alone, sintilimab combined with pemetrexed and cisplatin showed significant and clinically meaningful improvement of progression-free survival with an optimal safety profile. Sintilimab plus IBI305 plus chemotherapy continued to show progression-free survival benefit compared with chemotherapy alone in this second interim analysis with an additional 8-month follow-up.National Natural Science Foundation of China, Shanghai Municipal Science & Technology Commission Research Project, and Innovent Biologics.For the Chinese translation of the abstract see Supplementary Materials section.Copyright © 2023 Elsevier Ltd. All rights reserved.

基金：
This study was funded by National Natural Science Foundation of China (82030045 to SL), Shanghai Municipal Science & Technology Commission Research Project (19411950500 to SL), and Innovent Biologics. Editorial support for this manuscript was provided by Xiaoyun Wang, an employee of Innovent Biologics.
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出版当年[2023]版：
大类 | 1 区 医学
小类 | 1 区 危重病医学 1 区 呼吸系统
最新[2023]版：
大类 | 1 区 医学
小类 | 1 区 危重病医学 1 区 呼吸系统
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出版当年[2023]版：
Q1 CRITICAL CARE MEDICINE Q1 RESPIRATORY SYSTEM
最新[2023]版：
Q1 CRITICAL CARE MEDICINE Q1 RESPIRATORY SYSTEM

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第一作者：
第一作者机构： [1]Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: shunlu@sjtu.edu.cn. [*1]Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
通讯作者：
通讯机构： [1]Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: shunlu@sjtu.edu.cn. [*1]Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
推荐引用方式(GB/T 7714)：
Lu Shun,Wu Lin,Jian Hong,et al.Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial[J].LANCET RESPIRATORY MEDICINE.2023,11(7):624-636.doi:10.1016/S2213-2600(23)00135-2.
APA：
Lu Shun,Wu Lin,Jian Hong,Cheng Ying,Wang Qiming...&He Yue.(2023).Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial.LANCET RESPIRATORY MEDICINE,11,(7)
MLA：
Lu Shun,et al."Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial".LANCET RESPIRATORY MEDICINE 11..7(2023):624-636

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